{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T20:45:38Z","timestamp":1790109938314,"version":"4.0.1"},"reference-count":47,"publisher":"Georg Thieme Verlag KG","issue":"07","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Horm Metab Res"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Despite most of the prolactinomas can be treated with endocrine therapy and\/or surgery, a significant percentage of these tumors can be resistant to endocrine treatments and\/or recur with prominent invasion into the surrounding anatomical structures. Hence, clinical, pathological, and molecular definitions of aggressive prolactinomas are important to guide for classical and novel treatment modalities. In this review, we aimed to define molecular endocrinological features of dopamine agonist-resistant and aggressive prolactinomas for designing future multimodality treatments. Besides surgery, temozolomide chemotherapy and radiotherapy, peptide receptor radionuclide therapy, estrogen pathway modulators, progesterone antagonists or agonists, mTOR\/akt inhibitors, pasireotide, gefitinib\/lapatinib, everolimus, and metformin are tested in preclinical models, anecdotal cases, and in small case series. Moreover, chorionic gonadotropin, gonadotropin releasing hormone, TGF\u03b2 and PRDM2 may seem like possible future targets for managing aggressive prolactinomas. Lastly, we discussed our management of a unique prolactinoma case by asking which tumors\u2019 proliferative index (Ki67) increased from 5\u20136% to 26% in two subsequent surgeries performed in a 2-year period, exerted massive invasive growth, and secreted huge levels of prolactin leading up to levels of 1 605 671\u2009ng\/dl in blood.<\/jats:p>","DOI":"10.1055\/a-1525-2131","type":"journal-article","created":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T00:16:56Z","timestamp":1626740216000},"page":"413-424","source":"Crossref","is-referenced-by-count":16,"title":["Treatment Strategies for Dopamine Agonist-Resistant and Aggressive Prolactinomas: A Comprehensive Analysis of the Literature"],"prefix":"10.1055","volume":"53","author":[{"given":"Ramazan","family":"Sari","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Acibadem Hospital, Maslak, Istanbul, Turkey"},{"name":"Avrasya University, Health Sciences Faculty, Trabzon, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7804-4087","authenticated-orcid":false,"given":"Meric A.","family":"Altinoz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Acibadem University, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eylem Burcu Kahraman","family":"Ozlu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Acibadem Hospital, Maslak, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aydin","family":"Sav","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yeditepe University, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayca Ersen","family":"Danyeli","sequence":"additional","affiliation":[{"name":"Department of Pathology, Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozdil","family":"Baskan","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Hospital, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozlem","family":"Er","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilhan","family":"Elmaci","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Acibadem Hospital, Maslak, Istanbul, Turkey"},{"name":"Department of Neurosurgery, Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2021,7,19]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1177\/1078155215569556","article-title":"Temozolomide retreatment in a recurrent prolactin-secreting pituitary adenoma: Hormonal and radiographic response","volume":"22","author":"R E Strowd","year":"2016","journal-title":"J Oncol Pharm Pract"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"544","DOI":"10.4103\/0973-1482.137962","article-title":"Identification of human prolactinoma related genes by DNA microarray","volume":"10","author":"L Zhao","year":"2014","journal-title":"J Cancer Res Ther"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1080\/17446651.2019.1596024","article-title":"Clinical management of difficult to treat macroprolactinomas","volume":"14","author":"N Sahakian","year":"2019","journal-title":"Expert Rev Endocrinol Metab"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1159\/000499382","article-title":"Clinical, Pathological, and Molecular Factors of Aggressiveness in Lactotroph Tumours","volume":"109","author":"J Trouillas","year":"2019","journal-title":"Neuroendocrinology"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"477","DOI":"10.14310\/horm.2002.1380","article-title":"What causes a prolactinoma to be aggressive or to become a pituitary carcinoma?","volume":"11","author":"J Phillips","year":"2012","journal-title":"Hormones (Athens)"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s11060-013-1270-8","article-title":"Management of medically refractory prolactinoma","volume":"117","author":"M E Molitch","year":"2014","journal-title":"J Neurooncol"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"282","DOI":"10.4183\/aeb.2017.282","article-title":"Low O6-Methylguanine-DNA Methytransferase (mgmt) and Pan-Cytokeratin (Pan-Ck) expression via immunohistochemistry in pituitary adenomas","volume":"13","author":"R Basaran","year":"2017","journal-title":"Acta Endocrinol (Buchar)"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"e8733","DOI":"10.1097\/MD.0000000000008733","article-title":"Treatment of aggressive prolactinoma with temozolomide: A case report and review of literature up to date","volume":"96","author":"C Chen","year":"2017","journal-title":"Medicine (Baltimore)"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.clineuro.2017.09.009","article-title":"Whorling-sclerosing meningioma. A review on the histological features of a rare tumor including an illustrative case","volume":"162","author":"I Elmaci","year":"2017","journal-title":"Clin Neurol Neurosurg"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0090-3019(97)00458-8","article-title":"Malignant prolactinoma: case report and review of the literature","volume":"51","author":"A Popadi\u0107","year":"1999","journal-title":"Surg Neurol"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1210\/jcem.85.1.6253","article-title":"Malignant prolactinoma discovered by D2 receptor imaging","volume":"85","author":"P Petrossians","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"ref12","first-page":"e658","article-title":"Treatment of Aggressive Prolactin-Secreting Pituitary Adenomas with Adjuvant Temozolomide Chemotherapy: A Review","volume":"8","author":"M Moisi","year":"2016","journal-title":"Cureus"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s11102-019-00971-x","article-title":"Role of gamma knife radiosurgery in the treatment of prolactinomas","volume":"22","author":"J Je\u017ekov\u00e1","year":"2019","journal-title":"Pituitary"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1530\/EJE-16-0979","article-title":"Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas","volume":"176","author":"H Lasolle","year":"2017","journal-title":"Eur J Endocrinol"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"616339","DOI":"10.3389\/fendo.2021.616339","article-title":"Case Report: Temozolomide Treatment of Refractory Prolactinoma Resistant to Dopamine Agonists","volume":"12","author":"H Tang","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s11102-016-0745-y","article-title":"How effective is temozolomide for treating pituitary tumours and when should it be used?","volume":"20","author":"C Halevy","year":"2017","journal-title":"Pituitary"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"E1761","DOI":"10.1227\/NEU.0b013e318217161a","article-title":"A mechanism of acquiring temozolomide resistance during transformation of atypical prolactinoma into prolactin-producing pituitary carcinoma: Case report","volume":"68","author":"M Murakami","year":"2011","journal-title":"Neurosurgery"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"334","DOI":"10.3389\/fendo.2019.00334","article-title":"The Treatment of Refractory Pituitary Adenomas","volume":"10","author":"C Dai","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1530\/EC-19-0065","article-title":"Peptide receptor radionuclide therapy for aggressive pituitary tumors: A monocentric experience","volume":"8","author":"G Giuffrida","year":"2019","journal-title":"Endocr Connect"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1530\/JOE-16-0371","article-title":"Sex differences in the development of prolactinoma in mice overexpressing hCG\u03b2: Role of TGF\u03b21","volume":"232","author":"E Y Faraoni","year":"2017","journal-title":"J Endocrinol"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1007\/s11102-020-01029-z","article-title":"Expression patterns of ER\u03b166 and its novel variant isoform ER\u03b136 in lactotroph pituitary adenomas and associations with clinicopathological characteristics","volume":"23","author":"F Mahboobifard","year":"2020","journal-title":"Pituitary"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1038\/s41467-020-16052-8","article-title":"Somatic SF3B1 hotspot mutation in prolactinomas","volume":"11","author":"C Li","year":"2020","journal-title":"Nat Commun"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1111\/and.12317","article-title":"Diagnosis of prolactinoma in two male-to-female transsexual subjects following high-dose cross-sex hormone therapy","volume":"47","author":"F S Cunha","year":"2015","journal-title":"Andrologia"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.3390\/ijms21062024","article-title":"Pituitary Hyperplasia, Hormonal Changes and Prolactinoma Development in Males Exposed to Estrogens-An Insight From Translational Studies","volume":"21","author":"B \u0160o\u0161i\u0107-Jurjevi\u0107","year":"2020","journal-title":"Int J Mol Sci"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1677\/ERC-10-0016","article-title":"Enhanced LH action in transgenic female mice expressing hCGbeta-subunit induces pituitary prolactinomas; the role of high progesterone levels","volume":"17","author":"P Ahtiainen","year":"2010","journal-title":"Endocr Relat Cancer"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"BSR20191330","DOI":"10.1042\/BSR20191330","article-title":"17\u03b2-estradiol binding to ER\u03b1 promotes the progression of prolactinoma through estrogen-response element-induced CaBP-9k up-regulation","volume":"40","author":"J Liu","year":"2020","journal-title":"Biosci Rep"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s11102-019-00987-3","article-title":"Dopamine agonist resistant prolactinomas: any alternative medical treatment?","volume":"23","author":"P Souteiro","year":"2020","journal-title":"Pituitary"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.1177\/0300060519848916","article-title":"Increased expression of aromatase cytochrome P450 enzyme is associated with prolactinoma invasiveness in post-menopausal women","volume":"47","author":"Y X Su","year":"2019","journal-title":"J Int Med Res"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"684","DOI":"10.4158\/EP-2018-0321","article-title":"The effect of raloxifene on serum prolactin level in patients w\u0131th prolactinoma","volume":"25","author":"C Choudhary","year":"2019","journal-title":"Endocr Pract"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s11060-013-1351-8","article-title":"Effects of the estrogen receptor antagonist fulvestrant on F344 rat prolactinoma models","volume":"116","author":"L Cao","year":"2014","journal-title":"J Neurooncol"},{"key":"ref31","first-page":"4037","article-title":"Estrogen receptor antagonist fulvestrant inhibits proliferation and promotes apoptosis of prolactinoma cells by regulating the IRE1\/XBP1 signaling pathway","volume":"18","author":"C Wang","year":"2018","journal-title":"Mol Med Rep"},{"key":"ref32","first-page":"5364","article-title":"Fulvestrant inhibits the glycolysis of prolactinoma GH3 cells by downregulating IRE1\/XBP1 signaling pathway","volume":"22","author":"C Wang","year":"2018","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/onc.2016.264","article-title":"mTOR promotes pituitary tumor development through activation of PTTG1","volume":"36","author":"R Chen","year":"2017","journal-title":"Oncogene"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"R73","DOI":"10.1530\/JOE-15-0451","article-title":"The pituitary TGF\u03b21 system as a novel target for the treatment of resistant prolactinomas","volume":"228","author":"M V Recouvreux","year":"2016","journal-title":"J Endocrinol"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.brainres.2018.07.024","article-title":"Role of TGF-\u03b21\/Smad3-mediated fibrosis in drug resistance mechanism of prolactinoma","volume":"1698","author":"B Hu","year":"2018","journal-title":"Brain Res"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1530\/ERC-18-0409","article-title":"mPRs represent a novel target for PRL inhibition in experimental prolactinomas","volume":"26","author":"M A Camilletti","year":"2019","journal-title":"Endocr Relat Cancer"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"K21","DOI":"10.1530\/EJE-19-0279","article-title":"Excellent response to pasireotide therapy in an aggressive and dopamine-resistant prolactinoma","volume":"181","author":"E C Coopmans","year":"2019","journal-title":"Eur J Endocrinol"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.ando.2018.07.013","article-title":"Pasireotide: A potential therapeutic alternative for resistant prolactinoma","volume":"80","author":"H Lasolle","year":"2019","journal-title":"Ann Endocrinol (Paris)"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1007\/s12020-013-0093-x","article-title":"Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors","volume":"46","author":"O Cooper","year":"2014","journal-title":"Endocrine"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1097\/MED.0000000000000344","article-title":"Role of tyrosine kinase inhibitors in the treatment of pituitary tumours: from bench to bedside","volume":"24","author":"A Ben-Shlomo","year":"2017","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"e917","DOI":"10.1210\/clinem\/dgaa805","article-title":"EGFR\/ErbB2-Targeting Lapatinib Therapy for Aggressive Prolactinomas","volume":"106","author":"O Cooper","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1186\/s12885-015-1267-0","article-title":"Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas","volume":"15","author":"H Gao","year":"2015","journal-title":"BMC Cancer"},{"key":"ref44","doi-asserted-by":"publisher","DOI":"10.1159\/000515801","article-title":"miRNA-mediated Drug Repurposing Unveiled Potential Candidate Drugs for Prolactinoma Treatment","author":"B Aydin","year":"2021","journal-title":"Neuroendocrinology"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/onc.2016.264","article-title":"mTOR promotes pituitary tumor development through activation of PTTG1","volume":"36","author":"R Chen","year":"2017","journal-title":"Oncogene"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.wneu.2017.01.052","article-title":"Bromocriptine Induces Autophagy-Dependent Cell Death in Pituitary Adenomas","volume":"100","author":"X Geng","year":"2017","journal-title":"World Neurosurg"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1210\/jc.2018-02461","article-title":"Effect of Everolimus in Treatment of Aggressive Prolactin-Secreting Pituitary Adenomas","volume":"104","author":"D Zhang","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1093\/hmg\/ddy396","article-title":"Association of prolactin receptor (PRLR) variants with prolactinomas","volume":"28","author":"C M Gorvin","year":"2019","journal-title":"Hum Mol Genet"}],"container-title":["Hormone and Metabolic Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-1525-2131.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T07:04:58Z","timestamp":1699254298000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-1525-2131"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7]]},"references-count":47,"journal-issue":{"issue":"07","published-online":{"date-parts":[[2021,7,19]]},"published-print":{"date-parts":[[2021,7]]}},"URL":"https:\/\/doi.org\/10.1055\/a-1525-2131","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0018-5043","1439-4286"],"issn-type":[{"value":"0018-5043","type":"print"},{"value":"1439-4286","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7]]}}}